Johanson–Blizzard syndrome

Signs and symptoms

The most prominent effect of Johanson–Blizzard syndrome is exocrine pancreatic insufficiency, which involves decreased secretion of lipases and pancreatic juices such as trypsin and trypsinogen, leading to malabsorption of fats and disruptions in glucagon secretion and its response to hypoglycemia caused by insulin activity. This insufficiency can stem from congenital replacement of pancreatic acini with fatty tissue, impaired apoptosis, and chronic inflammatory damage, necrosis, and fibrosis; near total replacement of the pancreas with fatty tissue has been reported and can be progressive and sometimes fatal. Endocrine insufficiency of the pancreas also occurs, though it is often less common and less pronounced, and may involve connective tissue buildup in the islets of Langerhans, fatty replacement of the islets, or improper nerve signaling, resulting in diabetes mellitus. Ductular output of fluids and electrolytes, as well as moderate to normal levels of functioning bicarbonate, are preserved in many cases.

Genetics

Johanson–Blizzard syndrome follows an autosomal recessive inheritance pattern caused by loss-of-function mutations in the UBR1 gene, which encodes a ubiquitin ligase enzyme. The defective gene is located on an autosome at locus 15q15.2, spanning about 161 kb and containing 47 exons.

Two copies of the defective gene, one from each parent, are required for the disorder; carriers typically show no symptoms. UBR1 encodes one of at least four functionally overlapping E3 ubiquitin ligases of the N-end rule pathway, a conserved proteolytic system that destabilizes N-terminal residues. The protein binds to destabilizing N-terminal residues of substrate proteins to form substrate-linked multiubiquitin chains, inducing metabolic instability through degradation signals called N-degrons.

Pathophysiology

Mutations in the UBR1 gene cause Johanson–Blizzard syndrome by disrupting the function of one of several ubiquitin ligase enzymes in the N-end rule pathway. Ubiquitin, a protein common to eukaryotic organisms, tags target proteins for degradation by proteasomes through a process called polyubiquitination, where a chain of ubiquitin molecules is attached to the target protein. This signals the proteasome to break down the protein via proteolysis, a mechanism crucial for non-lysosomal degradation of intracellular proteins and for regulating cell division, cell signaling, apoptosis, DNA maintenance, inflammatory response, and developmental quality control. The N-end rule pathway, part of the ubiquitin system, relates a protein's stability to the identity of its N-terminal amino acid.

Treatment

There is no cure for Johanson–Blizzard syndrome, but management of specific symptoms can be effective. Pancreatic insufficiency and malabsorption are treated with pancreatic enzyme replacement therapy, such as pancrelipase supplementation. Craniofacial and skeletal deformities may require surgical correction through bone grafts and osteotomy procedures, while sensorineural hearing loss can be managed with hearing aids and educational services for the hearing impaired. Special education, counseling, and occupational therapy are used for intellectual disabilities.

Did You Know?

• Saccharomyces cerevisiae contains regions essential for recognition of N-end rule substrates by the UBR1 protein.
• Rabbit reticulocyte tryptic peptides were used to purify E3α.